The response of an individual to tumor cells involves the reactions and counteractions mediated by both cellular and humoral arms of the immune system. Tumor cell growth may represent a disturbance in the equilibrium of the immune system that is pre-existing, and/or induced by the tumor cells themselves. However, most investigations to date have focused on the role of T cells in tumor immunity. The role of B cells in a tumor-bearing individual still remains unclear.
Previous studies have shown that lymph nodes regional to a primary tumor in cancer patients, and in in vivo experimental animal models of tumor development, can undergo a prominent expansion in the germinal centers (Eremin et al., 1980, Br. J. Cancer 41:62; Bertschmann et al., 1984, Br. J. Cancer 49:477-484). In these "involved" lymph nodes, there is often an increased number of immune cells that include B lymphocytes (B cells). However, the reason(s) for this observed B cell proliferative response remains unclear, and may be due to either activation and stimulation directly by tumor cells or tumor cell components, and/or indirectly by stimulation of T-helper cells which then activate and stimulate B cells. A recent study confirmed the increase in the number of B cells in lymph nodes regional to primary tumors (Ito et al., 1996, Immunobiol. 195:1-15). The number of B cells increase in the regional lymph nodes concomitantly with tumor development, and such B cells appear to be able to elicit anti-tumor immunity. In that regard, there are numerous reports that cancer patients have circulating antitumor antibodies (see, e.g., Carey et al., 1976, Proc. Natl. Acad. Sci. USA 73:3278-3282; Abe et al., 1989, Cancer Res. 80:271-276; Christensen et al., 1989, Int. J. Cancer 37:683-688). Thus, there appears that a humoral immune response towards tumor-associated antigens can be mounted in cancer patients. However, the role of the B cells in the host response to tumor, and the tumor associated antigens recognized by B cells, remain poorly defined.
Surgical removal of a primary tumor alone, thereby reducing the major portion of the tumor burden, is often inadequate to control regrowth or metastasis of the tumor; and hence often fails to significantly affect survival of a cancer patient. For example, of the more than 150,000 Americans who will develop colorectal carcinoma each year, it is estimated that 17% to 55% of them will develop or already have metastases in the liver (Zaveidsky et al., 1994, Am. Surgeon 60:929-933). Surgery, when possible, is used as a standard therapy for patients with isolated metastases (e.g., hepatic and/or pulmonary). After resection, the projected five year survival rate may range from 25-35%, the mean survival is about 31 months, and the 30-day mortality rate is about 4% (Wade, 1996, J. Am. Coll. Surg. 182:353-361). However, about 25% to 45% of patients who have had resection of their colorectal cancer later develop recurrences (Zaveidsky et al., 1994, supra). While new chemotherapeutics are being developed and tested for efficacy, many of the currently available cancer treatments are relatively ineffective. It has been reported that chemotherapy results in a durable response in only 4% of treated patients, and substantially prolongs the life of only an additional 3% of patients with advanced cancer (Smith et al., 1993, J. Natl. Cancer Inst. 85:1460-1474). Current treatments for metastases are both cost-prohibitive, relatively ineffective, and present with major toxicity. Regarding the latter and depending on the drug or drug combination used, systemic chemotherapy may result in one or more toxicities including hematologic, vascular, neural, gastro intestinal, renal, pulmonary, otologic, and lethal.
In contrast to solid, nonlymphoid tumors, there are numerous approaches and successes in treating B cell lymphoma (cancer cells of B cell origin). Such treatments include administration of immunologically active anti-CD20 antibodies to B cell lymphoma patients (see, e.g., U.S. Pat. No. 5,776,456); administration of an immunoconjugate comprising mAb Lym-1 coupled to ricin toxin A chain (see, e.g., U.S. Pat. No. 4,724,213); administration of an immunoconjugate comprising mAb LL2 (anti-CD22) coupled to chemotherapeutic agent (see, e.g., U.S. Pat. No. 5,789,554); and administration of an mAb alone, or an immunoconjugate comprising anti-CD19 mAb coupled to a chemo-therapeutic agent (see, e.g., Hekman et al., 1991, Cancer Immunol. Immunother. 32:364-372; Cancer Research Weekly, Jun. 20, 1994, p.21; Cancer Research Weekly, Apr. 15, 1991, p.26).
We have discovered that certain soluble tumor antigens, shed from tumor cells of solid, nonlymphoid tumors, are capable of inducing an immune response which promotes tumor progression (comprising one or more of tumor growth, invasion, and metastasis). This mechanism of promotion of tumor progression involves the specific type of immune response induced by certain classes of shed tumor antigen, as described in more detail herein. This specific immune response, a "pro-tumor immune response", comprises (a) the contact or presence of shed tumor antigen in relation to the cell surface of B cells; (b) activation of such B cells to proliferate; (c) differentiation of B cells into plasma cells which secrete antibody against shed tumor antigen ("anti-shed tumor antigen antibody") which can interact with shed antigen in forming immune complexes; and (d) such immune complexes can act indirectly via immune effector cells, and/or directly on the nonlymphoid tumor cells, to mediate tumor progression.
Therefore, a need exists for methods which may be used to therapeutically treat a pro-tumor immune response, by treating B cells, in an individual; particularly in an individual who has a solid, nonlymphoid tumor, or an individual who is at high risk (e.g., environmentally and/or genetically) for developing a solid, nonlymphoid tumor, or an individual who has been treated for a solid, nonlymphoid tumor and thereby inherently carries a risk of recurrence of such tumor.